Leptospirosis, a spirochetal disease, is a leading zoonotic cause of morbidity and mortality worldwide. It has traditionally been a rural-based disease of subsistence farmers and pastoralists, but the investigations of Yale University and Oswaldo Cruz Foundation (Fiocruz) in Brazil have raised awareness that leptospirosis has emerged as a cause of rat-borne epidemics in urban slum populations. Moreover, leptospirosis causes life- threatening disease and has become a major cause worldwide of pulmonary hemorrhage syndrome and acute kidney injury. To date, there is no effective prevention or control for leptospirosis in resource-poor settings. An effective vaccine would provide synergistic health and societal benefits by preventing transmission and disease in domestic animals and the risk of spill-over infections in humans. The major challenge has been developing a vaccine that protects against the nine species and >200 serovars which are agents for leptospirosis. In addition, a key knowledge gap for vaccine development is whether naturally-acquired immunity to reinfection occurs in humans. Our field investigations in Brazil have addressed this question and now provide the first evidence that naturally-acquired infection confers immunity against reinfection in populations residing in high- transmission slum settings. Furthermore, we produced motility-deficient mutant strains of L. interrogans and found that immunization with this attenuated strain conferred cross-protective immunity to infection with homologous and heterologous serovars in experimental animals. We developed novel whole L. interrogans proteome arrays to interrogate the immune response to infection and found that immunization with the attenuated strain in animals, as well as naturally acquired infection in humans, induce antibodies to a restricted repertoire of Leptospira proteins. These findings form the basis for our proposal, which builds on the infrastructure created in Brazil through NIH support since 1996, which includes a community site mobilized for long-term cohort studies, diagnostic and vaccine research laboratories, and a multidisciplinary team of collaborators. We propose to integrate field studies on the natural history with animal models of immunity, thus creating the opportunity to test hypotheses generated from our investigations of human populations. Our proposal aims to identify vaccine candidates and evaluate the feasibility of a universal vaccine approach for leptospirosis. In the 1st project aim, we will determine prospectively whether naturally-acquired infection in a cohort of slum residents induces robust anti-Leptospira protein responses and whether these responses are correlates of immunity to reinfection. In the 2nd project aim, we will identify the specific Leptospira proteins which elicit naturally-acquired and attenuated vaccine-mediated immunity and determine whether immunization with these antigens confers cross-protective immunity in animals. We expect to identify, as outcome of this proposal, novel human correlates of immunity and vaccine candidates for leptospirosis, which in turn will yield new intervention strategies for this important yet neglected infectious disease problem.